This invention relates to a method of enhancing diagnostic use of ultrasound by providing a microbubble contrast agent having a controlled fragility. Specific use of the methodology involves the enhancement of tissue perfusion imaging, measurement of physiological pressure, and delivery of drugs.
It is well known that microbubbles are efficient backscatterers of ultrasonic energy. Thus, microbubbles injected interstitially or into the bloodstream can enhance ultrasonic echographic imaging to aid in the visualization of biological structures such as the internal organs or the cardiovascular system. Contrast is achieved when acoustic impedance between two materials at an interface is different. Thus, the greater the impedance difference between the two materials the greater the intensity of the ultrasound echo. Since there is a large difference between the acoustic impedance of body tissue and gas, microbubbles offer excellent ultrasound contrast to aid in delineating biological structures that otherwise would be difficult to distinguish.
Over the past few years, a variety of methods have been developed for the manufacture of ultrasonic contrast agents. The processes for their fabrication usually involve spray drying, emulsion, or interfacial polymerization techniques. Typically, the result is a microbubble population having a range of diameters with either a fixed or an arbitrarily variable wall thickness. An ultrasonic contrast agent produced by one methodology, for example, may contain microbubbles where each has a shell wall of the same thickness regardless of its diameter. Alternatively, a different method of production may result in a microbubble population with wall thickness varying even between those microbubbles having the same diameter.
For many applications, a microbubble contrast agent with the aforementioned characteristics may not be optimal. For example, of major interest is the use of microbubbles administered intravenously to provide echographic contrast to the blood pool for enhanced imaging of the vascularized organs and structures, especially the heart. Hydrostatic pressures of the cardiovascular system can in many cases approach 250 mmHg. At such pressures, microbubbles within the population having relatively thinner walls could be subject to rupture and loss of internal gas. If this occurs before the agent reaches the imaging region, then the result is a degradation of contrast performance.
Further, an important aspect of imaging the cardiovascular system is the measurement of blood perfusion through the tissues of the heart. This is best accomplished by a procedure wherein systemically introduced microbubble agent is first cleared from a region of interest by exposure with an insonating signal having a power intensity sufficiently high to rupture and thus destroy the microbubbles that are present in the field. Reflow of agent into the region is then recorded using a relatively lower ultrasound power setting where the microbubbles are no longer being destroyed. In this case, microbubbles within the population having thicker walls may be so durable that they survive the high intensity ultrasound beam. Efficacy is reduced due to the residual contrast resulting from the remaining undamaged microbubbles still present in the imaging region.
Another application for which microbubbles having an arbitrary wall thickness may be unsuitable is in the field of ultrasonically mediated drug delivery. Conceptually, a microbubble agent is, through processing, internally loaded with a drug. The treated microbubbles are then injected intravenously and allowed to systemically circulate. An ultrasound signal of sufficient energy to rupture the drug containing microbubbles is applied to a region where the delivery of the drug is desired. The insonating beam destroys the microbubbles and thus releases its payload. However, a microbubble population having an arbitrary wall thickness could result in the drug being released prematurely or not at all. Those with thinner more fragile walls may rupture from hydrostatic pressure before reaching the site. Those with thicker more durable walls may not rupture at all.
A microbubble population with a fixed wall thickness but having a range of diameters would similarly be unsuitable for these applications. While the strength of a microbubble is a function of the thickness of its wall, it is also a function of its diameter. Thus, a relatively smaller microbubble would show more resistance to hydrostatic and acoustic pressures than would a relatively larger bubble having the same wall thickness.
A microbubble agent having a controlled fragility would therefore represent an improvement to the state of the art. For purposes here, the term xe2x80x9ccontrolled fragilityxe2x80x9d is taken to describe a microbubble population having the characteristic of being rupturable only when exposed to acoustic energy equal to or greater than a predetermined intensity. That is, below this acoustic intensity threshold, substantially all the microbubbles remain intact while above the acoustic intensity threshold the microbubbles rupture. Thus, the agent can be turned-on or turned-off by controlling the intensity of the insonating signal.
An ultrasonic contrast agent having a controlled fragility characteristic would be of benefit to blood profusion studies. After systemic injection, the agent would perfuse into the tissues of interest where it would provide image contrast. Acoustic intensity could then be increased above a predetermined value in order to rupture those microbubbles in the field. The ruptured microbubbles release the gas encapsulated within and the gas in turn quickly dissolves. The region would then be essentially devoid of contrast. The intensity could once again be reduced so that an image can be continuously recorded as a fresh supply of microbubbles from the systemic blood pool flowed into the region. Alternatively, when ultrasound modalities which rely on microbubble destruction to generate contrast, intermittent imaging at intensities designed to rupture the microbubbles may be used to monitor reperfusion of blood into the region.
Likewise, drug-containing microbubbles having a controlled fragility would provide increased efficacy because microbubble rupture, and hence, release of their contents would occur only at the region where the intensity of acoustic energy is greater than that needed for microbubble rupture.
If the ultrasound imaging agent is to be used in blood pool applications, it is preferred that the majority of the microbubbles have diameters within the range of about 1 to 10 microns. This will insure that the microbubbles are small enough to pass through the capillary system unimpeded.
A variety of ultrasound imaging modalities are available for use with echographic contrast agents. Among these modalities are B-mode (both fundamental and harmonic), power doppler, and pulse inversion imaging. Each is typically best suited to specific applications. Of those applications described above, one modality or another may be most suitable to use in concert with a microbubble agent having a controlled fragility. For example, power doppler techniques has been shown to provide good results for imaging myocardial perfusion when using high MI intermittent imaging techniques. Pulse inversion methods, on the other hand, are most suitable when low MI continuous mode imaging is used to monitor perfusion. A more detailed description of the different echographic imaging modalities can be found in the Handbook of Contrast Echocardiology by H. Becher et. al. (Becher, Harold and Peter N. Burns; Handbook of Contrast Echocardiography; 150 pp, 100 figures; (2000).)
A microbubble population having a controlled fragility is most useful as an ultrasound imaging agent when the microbubbles of the population are rupturable within a power range typical of diagnostic imaging. This range is typically what is required to produce a field having a Mechanical Index from about 0.1 to about 2.6.
It is an object of the present invention to provide an ultrasound contrast agent consisting of a microbubble population having a controlled fragility. Also provided is a method for echographic enhancement using a microbubble contrast agent having controlled fragility.
An ultrasound imaging agent composition is provided consisting of a microbubble population having a controlled fragility wherein the wall thickness of the outer shell of each microbubble forms a ratio with the microbubble diameter that is substantially the same as the wall thickness to diameter ratio of all other microbubbles in the population.
Methods of producing such a microbubble imaging agent composition incorporate emulsification techniques wherein the emulsion droplets formed in the process are microbubble precursors with each containing equal concentration of wall-forming material irrespective of droplet diameter. Thus, a larger droplet would contain wall-forming material that is greater in amount than a smaller droplet by a ratio that provides for a wall thickness that is linearly related to diameter. An ultrasound imaging agent so produced would contain microbubbles exhibiting equivalent resistance to the hydrostatic and acoustic stresses present in the ultrasound imaging field.
A method of echographic imaging using such an ultrasound imaging agent composition within a fluid-filled cavity, vessel or tissue comprises the steps of:
a. introducing a microbubble contrast agent consisting of a microbubble population having a constant wall thickness to diameter ratio that is characterized by a threshold intensity of ultrasonic power of microbubble rupture that is within the power range useful for diagnostic imaging, into said region of interest;
b. applying an ultrasonic signal to said region of interest at an applied power intensity greater than the threshold intensity;
The signal generated by the destruction of the microbubbles can also be ultrasonically recorded. The applied power intensity may also be reduced to less than the threshold intensity. Then the reflow of the microbubble agent into the region of interest can be measured.